Pentacyclic compounds

ABSTRACT

Compounds of formula (I), ##STR1## or an N-oxide or pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen, C 1-7  alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkenyl or C 1-4  alkyl substituted by C 2-7  alkenyl, C 2-7  alkynyl, C 3-7  cycloalkyl, hydroxy, thiol, C 1-4  alkoxy, C 1-4  alkylthio, carboxy, C 1-4  alkoxycarbonyl, C 1-4  alkanoyl, amino optionally substituted by one or two C 1-4  alkyl or by C 4-6  polymethylene optionally containing an oxygen or nitrogen atom, aminocarbonyl optionally N-substituted by one or two C 1-4  alkyl, or benzoyl or phenyl either being optionally ring-substituted by C 1-4  alkyl, C 1-4  alkoxy, halogen or trifluoromethyl, R 2  and R 3  are the same or different and are hydrogen, hydroxy, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, halogen or trifluoromethyl, m is 1 to 3 and n is 1 or 2, the hydrogen atom bonded to the C a  carbon atom being trans to the hydrogen atom bonded to the C b  carbon atom, having mood-modifying activity such as anti-depressant activity.

This application is a division of co-pending U.S. patent applicationSer. No. 472,218, filed Mar. 4, 1983, now U.S. Pat. No. 4,504,480.

This invention relates to novel pentacyclic compounds havingpharmacological activity, to processes and intermediates of use in theirpreparation, to pharmaceutical compositions containing them, and totheir use in the treatment of mammals.

U.K. Pat. No. 1,173,783 discloses compounds of formula (A); ##STR2##wherein R_(a) and R_(c) each represent a hydrogen or halogen atom, ahydroxy, lower acyloxy, alkyl or alkoxy group, or a trifluoromethylgroup, R_(b) represents hydrogen, a lower alkyl or aralkyl group, anaminoethyl or aminopropyl group N-substituted by one or more lower alkylgroups, or a lower alkyl group forming a substituent of an N-containingheterocyclic ring, the said ring being directly bonded to the nitrogenatom of the piperazine ring, and A represents a single bond, or amethylene, ethylene or --CH═CH-- group.

U.K. Pat. No. 1,229,252 discloses compounds of formula (B); ##STR3##wherein R_(d) and R_(f) represent hydrogen, halogen, hydroxy, acyloxy,lower alkoxy or lower alkyl or trifluoromethyl, R_(e) representshydrogen, lower alkyl, lower aralkyl, aminoethyl or aminopropyloptionally N-substituted by lower alkyl, or lower alkyl substituted by anitrogen-containing heterocyclic ring, and B represents oxygen, sulphur,or NRg, Rg representing lower alkyl.

The compounds of formulae (A) and (B) are disclosed as havinganti-inflammatory, anti-serotoninic, anti-histaminic, anti-phlogisticand cardiovascular activities. In addition, the compound of formula (A),wherein R_(a) and R_(c) are both hydrogen, R_(b) is methyl and A ismethylene, is commonly known as mianserin and is marketed as ananti-depressant agent for the treatment of depression in mammals.

U.K. Pat. No. 1,229,253 discloses compounds of formula (C); ##STR4##wherein R_(d), R_(e), R_(f) and B are as defined in relation to formula(B) above, and D and E are either hydrogen or together represent adouble bond between the nitrogen and carbon atoms to which they areattached, and functional derivatives thereof. Such compounds aredisclosed as having sedative, tranquilising and anti-depressantactivity.

U.S. Pat. No. 4,316,900 discloses compounds of formula (D); ##STR5## andsalts thereof derived from pharmaceutically acceptable acids or ammoniumor alkali metal bases, wherein R_(h), R_(j) and R_(k) are each hydrogenor lower alkyl, R_(i) is hydrogen, lower or higher alkyl, lower alkenyl,lower alkynyl, C₃₋₇ cycloalkyl, cycloalkenyl or lower alkyl substitutedby cycloalkyl, hydroxy, amino, mono- or di-lower alkylamino, carboxy,lower carbalkoxy, carbamoyl, mono- or di-lower alkyl carbamoyl, phenyl,lower alkanoyl or benzoyl, Ph is 1,2-phenylene unsubstituted orsubstituted by up to two members selected from lower alkyl, loweralkoxy, lower alkylthio, halogen and trifluoromethyl, G is loweralkylene separating both nitrogen atoms by 2 or 3 carbon atoms and R_(m)is hydrogen, lower alkyl, carboxy, lower carbalkoxy or lower alkylsubstituted by hydroxy, amino, mono- or di-lower alkylamino, and thelower alkoxycarbonyl, lower or higher alkanoyl, adamantoyl, carbamoyl,mono- or di-lower alkylcarbamoyl, C₃₋₇ cycloalkylcarbonyl or benzoylderivatives thereof, and the 2-N-oxide, 2-lower alkyl or 2-phenyl loweralkyl quaternaries and salts thereof derived from pharmaceuticallyacceptable acids or bases. Such compounds are described asanti-depressant agents suitable, for example, in the treatment ormanagement of mental depression in mammals.

A structurally distinct class of compounds has now been discovered whichcompounds are dibenz[b,e]azepines in which the azepine nitrogen atom andthe azepine carbon atom adjacent thereto are joined with C₁₋₃alkyleneaminomethylene to form a 5- to 7-membered ring, characterised bya methylene or ethylene bridge from the carbon atom of theaminomethylene moiety to the carbon atom of the benzo moiety that is inthe ortho-position to the azepine ring and that is on the same side as,and three carbon's distance from, the azepine nitrogen atom, the bridgethus forming a 5- or 6-membered ring. Such compounds, moreover, havebeen found to have pharmacological activity, in particularmood-modifying activity, such as anti-depressant activity.

Accordingly, the present invention provides a compound of formula (I);##STR6## or an N-oxide or pharmaceutically acceptable salt thereof,wherein R₁ is hydrogen, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenylor C₁₋₄ alkyl substituted by C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, hydroxy, thiol, C₁₋₄ alkoxy, C₁₋₄ alkylthio, carboxy, C₁₋₄alkoxycarbonyl, C₁₋₄ alkanoyl, amino optionally substituted by one ortwo C₁₋₄ alkyl or by C₄₋₆ polymethylene optionally containing an oxygenor nitrogen atom, aminocarbonyl optionally N-substituted by one or twoC₁₋₄ alkyl, or benzoyl or phenyl either being optionallyring-substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or trifluoromethyl,R₂ and R₃ are the same or different and are hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, halogen or trifluoromethyl, m is 1to 3 and n is 1 or 2, the hydrogen atom bonded to the C_(a) carbon atombeing trans to the hydrogen atom bonded to the C_(b) carbon atom.

Within the definition for R₁ is a sub-group, wherein R₁ is hydrogen,C₁₋₄ alkyl, C₁₋₄ alkyl substituted by amino optionally substituted byone or two C₁₋₄ alkyl or by C₄₋₆ polymethylene optionally containing anoxygen or nitrogen atom, or C₁₋₄ alkyl substituted by phenyl optionallysubstituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or trifluoromethyl.

When R₁ is C₁₋₄ alkyl substituted by phenyl optionally substituted ashereinbefore defined, examples of such optional substituents includemethyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo ortrifluoromethyl. Preferably, phenyl is unsubstituted.

When R₁ is C₁₋₄ alkyl substituted by amino optionally substituted ashereinbefore defined, examples of such optional substituents includemethyl and ethyl and, together with the nitrogen atom, piperidino andmorpholino.

Preferably, R₁ is hydrogen or C₁₋₄ alkyl, in particular C₁₋₄ alkyl, suchas methyl and ethyl.

Within the definition for R₂ and R₃ is a sub-group, wherein R₂ and R₃are the same or different and are hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,halogen or trifluoromethyl.

Preferred examples for R₂ and R₃ are hydrogen, hydroxy, methyl, ethyl,methoxy, ethoxy, bromo, chloro, fluoro and trifluoromethyl. Preferably,R₂ is hydrogen, methoxy, hydroxy, methyl or chloro and R₃ is hydrogen.

Preferably, m is 1 or 2.

Preferably, n is 1.

The compounds of the invention have chiral centres at the C_(a) andC_(b) carbon atoms and therefore can exist in enantiomeric forms. Thepresent invention extends to such enantiomers individually and asmixtures including racemates.

Particularly preferred compounds within formula (I) are the compounds ofthe examples described hereinafter or an N-oxide or pharmaceuticallyacceptable salt thereof. The most preferred compound of formula (I) istrans-12-methyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene,which is the compound prepared in Example 1, or an N-oxide orpharmaceutically acceptable salt thereof.

An N-oxide of a compound of formula (I) includes the oxide of eithernitrogen atom shown in formula (I) and the oxide of anynitrogen-containing substituent for R₁.

A pharmaceutically acceptable salt of a compound of formula (I) includesan acid addition salt of either nitrogen atom shown in formula (I) andof any nitrogen-containing substituent for R₁, the acid addition saltbeing derived from a pharmaceutically acceptable inorganic or organicacid, such as hydrochloric acid, hydrobromic acid, sulphuric acid,maleic acid and acetic acid. A pharmaceutically acceptable salt of acompound of formula (I) also includes alkali metal or alkaline earthmetal salts of any carboxy-containing substituent for R₁. Examples ofsuch salts include potassium, sodium, calcium and magnesium salts.

The present invention also provides a process for preparing a compoundof formula (I), as defined hereinbefore, which comprises cyclising acompound of formula (II); ##STR7## wherein R₂, R₃, m, n and theconfiguration of the C_(a) and C_(b) hydrogen atoms are as definedhereinbefore, R₁ ' is R₁ or C₁₋₄ alkoxycarbonyl, phenoxycarbonyl orbenzyloxycarbonyl and G is formyl, carboxy or a C₁₋₄ alkyl ester thereofor is CH₂ L₁, L₁ being a leaving group; in the case when R₁ ' is C₁₋₄alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, converting R₁ 'into R₁ ; in the case when G is formyl, carboxy or a C₁₋₄ alkyl esterthereof, reducing the resulting carbonyl or hydroxymethylene moiety to amethylene moiety; optionally converting R₁, R₂ or R₃ in the resultingcompound of formula (I) into another R₁, R₂ or R₃ ; and optionallyforming an N-oxide or pharmaceutically acceptable salt thereof.

Preferred examples of the leaving group (L₁) include hydroxy, bromo,chloro, C₁₋₄ alkoxy, C₁₋₄ alkanoyloxy, C₁₋₄ alkoxycarbonyloxy, tosyloxyand mesyloxy.

When the leaving group (L₁) is hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkanoyloxy,C₁₋₄ alkoxycarbonyloxy, tosyloxy or mesyloxy, or when G is formyl,carboxy or a C₁₋₄ alkyl ester thereof, the cyclisation reaction ispreferably carried out in the presence of a dehydrating agent, forexample orthophosphoric acid or methane sulphonic acid containingphosphorus pentoxide.

When the leaving group (L₁) is bromo or chloro, the cyclisation reactionis preferably carried out in the presence of a Lewis acid, such asaluminium trichloride.

When R₁ ' is C₁₋₄ alkoxycarbonyl, pheoxycarbonyl or benzyloxycarbonyl,the process proceeds through an intermediate of formula (III); ##STR8##wherein R₂, R₃, m, n and the configuration of the C_(a) and C_(b)hydrogen atoms are as defined hereinbefore and R₄ is C₁₋₄ alkyl, phenylor benzyl.

The conversion of the C₁₋₄ alkoxycarbonyl, phenoxycarbonyl orbenzyloxycarbonyl group into R₁ may be carried out in accordance withany appropriate known procedure. For example, the group may behydrolysed with concomitant decarboxylation using ethanolic sodiumhyroxide to give a compound of formula (I), wherein R₁ is hydrogen,which may then optionally be converted into another R₁, as describedhereinafter. Alternatively, the group may be reduced using, for example,lithium aluminium hydride in a solvent, for example, ether ortetrahydrofuran, to give a compound of formula (I), wherein R₁ ismethyl.

When G is formyl, carboxy or a C₁₋₄ alkyl ester thereof, the processproceeds through an intermediate of formula (IV); ##STR9## wherein R₁ ',R₂, R₃, m, n and the configuration of the C_(a) and C_(b) hydrogen atomsare as defined hereinbefore and J is CO or CHOH, when G in formula (II)is carboxy or a C₁₋₄ alkyl ester thereof, or is CHOH, when G in formula(II) is formyl.

The reduction of the resulting carbonyl or hydroxymethylene moiety maybe carried out using, for example, catalytic hydrogenation.

Examples of an optional conversion of R₁ in a compound of formula (I)into another R₁ include the conversion of C₁₋₄ alkyl substituted byhydroxy into C₁₋₄ alkyl substituted by thiol by, for example, firstforming a C₁₋₄ alkyl halide, such as the chloride, and then reacting theC₁₋₄ alkyl halide with potassium hydrogen sulphide, or into C₁₋₄ alkylsubstituted by C₁₋₄ alkoxy using, for example, sodium hydride and a C₁₋₄alkyl halide; the conversion of C₁₋₄ alkyl substituted by thiol intoC₁₋₄ alkyl substituted by C₁₋₄ alkylthio using, for example, a base anda C₁₋₄ alkyl halide; the conversion of C₁₋₄ alkyl substituted by C₁₋₄alkoxycarbonyl into C₁₋₄ alkyl substituted by carboxy by hydrolysis; theconversion of C₁₋₄ alkyl substituted by carboxy into C₁₋₄ alkylsubstituted by aminocarbonyl optionally N-substituted by one or two C₁₋₄alkyl by, for example, first forming the carboxylic acid halide, such asthe chloride, and then reacting the acid halide with ammonia optionallysubstituted by one or two C₁₋₄ alkyl; and the conversion of C₁₋₃ alkylsubstituted by aminocarbonyl optionally N-substituted by one or two C₁₋₄alkyl into C₁₋₄ alkyl substituted by amino optionally substituted by oneor two C₁₋₄ alkyl by reduction.

An important sub-class of an optional conversion of R₁ is that in whicha compound of formula (I), wherein R₁ is hydrogen, is converted intoanother compound of formula (I), wherein R₁ is as follows:

(a) wherein R₁ is C₁₋₇ alkyl, by alkylation with a C₁₋₇ alkyl halide ina solvent, such as acetone, in the presence of a base, or by reductiveC₁₋₇ alkylation in which a mixture of a compound of formula (I), whereinR₁ is hydrogen, and a C₁₋₇ aldehyde is reduced catalytically or withsodium cyanoborohydride in a solvent, such as ethanol, or by C₂₋₇acylation using a carboxylic acid chloride or anhydride in a solvent,such as methylene dichloride, in the presence of an organic or inorganicbase, for example pyridine, triethylamine or potassium carbonate, andthen reduction of the C₂₋₇ acylated derivative with, for example,lithium aluminium hydride;

(b) wherein R₁ is C₃₋₇ cycloalkyl, by reductive alkylation, as describedin paragraph (a), using a C₃₋₇ cycloalkanone;

(c) wherein R₁ is C₃₋₇ cycloalkenyl, by reaction with a C₃₋₇cycloalkenyl halide, such as a C₃₋₇ cycloalkenyl bromide, when thehalide atom is allylic, or by reductive alkylation, as described inparagraph (a), using a C₃₋₇ cycloalkenone;

(d) wherein R₁ is C₁₋₄ alkyl substituted by C₂₋₇ alkenyl or C₂₋₇alkynyl, by reaction with a C₂₋₁₁ alkenyl or C₂₋₁₁ alkynyl halide, suchas a C₂₋₁₁ alkenyl or C₂₋₁₁ alkynyl bromide, in a solvent, such asacetone, in the presence of a base, such as potassium carbonate;

(e) wherein R₁ is C₁₋₄ alkyl substituted by C₃₋₇ cycloalkyl, byacylation with a compound of formula (V); ##STR10## in which p is 1 to5, q is 0 to 3 and L₂ is a leaving group, such as chloro, and thenreduction of the acylated derivative, as described in paragraph (a);

(f) wherein R₁ is C₁₋₄ alkyl substituted by hydroxy, by reaction withaqueous formaldehyde when R₁ is hydroxymethyl, by reaction with ethyleneoxide when R₁ is hydroxyethyl, or by Michael addition with ethylacrylate or by reaction with ethyl ω-bromobutyrate and reduction of theester with lithium aluminium hydride when R₁ is respectivelyhydroxypropyl or hydroxybutyl;

(g) wherein R₁ is C₁₋₄ alkyl substituted by C₁₋₄ alkoxycarbonyl, byreaction with a compound of formula (VI);

    L.sub.3 --(CH.sub.2).sub.r --CO.sub.2 R.sub.5              (VI)

in which R₅ is C₁₋₄ alkyl, L₃ is a leaving group, such as bromo, and ris 1 to 4, in a solvent, such as methylene dichloride, in the presenceof a base, or by Michael addition with a C₁₋₄ alkyl acrylate when R₁ isethyl substituted by C₁₋₄ alkoxycarbonyl;

(h) wherein R₁ is C₁₋₄ alkyl substituted by C₁₋₄ alkanoyl, by reactionwith a C₁₋₄ alkanoyl C₁₋₄ alkyl halide or by Michael addition with aC₁₋₄ alkyl vinyl ketone when R₁ is ethyl substituted by C₁₋₄ alkanoyl;

(i) wherein R₁ is C₁₋₄ alkyl substituted by amino optionally substitutedby one or two C₁₋₄ alkyl or by C₄₋₆ polymethylene optionally containingan oxygen or nitrogen atom, by reaction with a compound of formula(VII);

    L.sub.4 --(CH.sub.2).sub.r --NR.sub.6 R.sub.7              (VII)

in which R₆ and R₇ are hydrogen or C₁₋₄ alkyl or together are C₄₋₆polymethylene optionally containing an oxygen or nitrogen atom, L₄ is aleaving group, such as chloro, and r is as hereinbefore defined, in asolvent, such as acetone, in the presence of a base, or by reaction withbromoacetyl bromide, reaction with HNR₆ R₇, R₆ and R₇ being as definedhereinbefore, and then reduction, as described in paragraph (a), when R₁is ethyl substituted by amino optionally substituted by one or two C₁₋₄alkyl or by C₄₋₆ polymethylene optionally containing an oxygen ornitrogen atom;

(j) wherein R₁ is C₁₋₄ alkyl substituted by aminocarbonyl optionallyN-substituted by one or two C₁₋₄ alkyl, by reaction with a compound offormula (VIII);

    L.sub.5 --(CH.sub.2).sub.r --CO--NR.sub.8 R.sub.9          (VIII)

in which L₅ is a leaving group, such as halide, in particular bromide, ris as hereinbefore defined and R₈ and R₉ are hydrogen or C₁₋₄ alkyl;

(k) wherein R₁ is C₁₋₄ alkyl substituted by benzoyl or phenyl eitherbeing optionally substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen ortrifluoromethyl, by reaction with the correspondingly substituted C₁₋₄alkyl halide, such as the bromide.

The present invention extends to all of the above conversions, whethersingly or in combination, and to the intermediates used therein, whichtogether are of formula (IX); ##STR11## wherein R₂, R₃, m, n and theconfiguration of the C_(a) and C_(b) hydrogen atoms are as definedhereinbefore and R₁₀ is C₁₋₄ alkyl substituted by halogen orhalocarbonyl or is C₁₋₄ alkylcarbonyl, C₃₋₇ cycloalkylcarbonyl, C₃₋₇cycloalkyl C₁₋₃ alkylcarbonyl or halo C₁₋₄ alkylcarbonyl.

When R₁ in formula (II) is a functional group that may possiblyinterfere with the course of the reaction or that may not possiblysurvive it, then it is preferred to carry out the preparation of acompound of formula (I) with R₁ as hydrogen and subsequently to convertthe hydrogen atom into the desired group for R₁ by, for example, one ormore of the conversions described hereinbefore.

An example of an optional conversion of R₂ or R₃ in a compound offormula (I) into another R₂ or R₃ is the conversion of C₁₋₄ alkoxy intohydroxy using, for example, aqueous hydrobromic acid.

The optional formation of an N-oxide may be carried out by reacting acompound of formula (I) with an organic peracid, such asm-chloroperbenzoic acid.

The optional formation of a pharmaceutically acceptable acid additionsalt of a compound of formula (I) may be carried out by simple reactionof a compound of formula (I) with a pharmaceutically acceptable acid.

The optional formation of a pharmaceutically acceptable alkali oralkaline earth metal salt of a compound of formula (I), wherein R₁ is acarboxy-containing substituent, may be carried out by reaction of acompound of formula (I) with an alkali or alkaline earth metal or thehydroxide thereof.

The present invention provides a second process for preparing a compoundof formula (I), as defined hereinbefore, which comprises reacting acompound of formula (X); ##STR12## wherein R₁ ', R₂, R₃, n and theconfiguration of the C_(a) and C_(b) hydrogen atoms are as definedhereinbefore, with a compound of formula (XI);

    L.sub.7 --(CO).sub.s --(CH.sub.2).sub.t --(CO).sub.u --L.sub.8 (XI)

wherein L₇ and L₈ are leaving groups, s and u are 0 or 1 and t is 0 to 3such that s+t+u is 1 to 3; in the case when s or u is 1, reducing thecarbonyl moiety to give a methylene moiety; in the case when R₁ ' isC₁₋₄ alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, converting R₁' into R₁ ; optionally converting R₁, R₂ or R₃ in the resulting compoundof formula (I) into another R₁, R₂ or R₃ ; and optionally forming anN-oxide or pharmaceutically acceptable salt thereof.

Preferred examples of the leaving groups (L₇ and L₈) include halo, suchas chloro and bromo, C₁₋₄ alkoxy, and labile acyloxy, such as mesyloxyand tosyloxy.

Preferred examples of a compound of formula (XI) include diethyloxalate, bromoacetyl bromide, methyl bromoacetate, dibromoethane, oxalylchloride and phosgene. Apart from diethyl oxalate which is used neat,all these compounds are reacted with a compound of formula (X), when R₁' is other than C₁₋₄ alkoxycarbonyl, phenoxycarbonyl orbenzyloxycarbonyl, in a solvent, for example, benzene, toluene,methylene dichloride, dimethyl sulphoxide or diethyl ether, in thepresence of an organic or inorganic base, for example triethylamine,pyridine, picoline or potassium carbonate. On the other hand, when R₁ 'is C₁₋₄ alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, thereaction at the carbamate nitrogen requires a solvent, such asdimethylformamide, and the presence of a strong base, such as sodiumhydride.

When s or u is 1, the process proceeds through an intermediate offormula (XII); ##STR13## wherein R₁ ', R₂, R₃, n and the configurationof the C_(a) and C_(b) hydrogen atoms are as defined hereinbefore ands', t' and u' respectively are the same as s, t and u, as definedhereinbefore, with the proviso that at least one of s and u is 1.

The reduction of the carbonyl moiety to give a methylene moiety ispreferably carried out with diborane or lithium aluminium hydride.

When m in formula (I) is 2 or 3, however, s and u are preferably 0, thusavoiding the need for an additional reduction step.

The conversion of R₁ ', when C₁₋₄ alkoxycarbonyl, phenoxycarbonyl orbenzyloxycarbonyl, into R₁, the optional conversion of R₁, R₂ or R₃ inthe resulting compound of formula (I) into another R₁, R₂ or R₃, and theoptional formation of an N-oxide or pharmaceutically acceptable salt maybe carried out as described hereinbefore.

The present invention provides a third process for preparing a compoundof formula (I), wherein m is 2, which comprises cyclising a compound offormula (XIII); ##STR14## wherein R₁ ', R₂, R₃, n and the configurationof the C_(a) and C_(b) hydrogen atoms are as defined hereinbefore andone of V and W is hydrogen and the other is (CH₂)₂ L₉, L₉ being aleaving group; in the case when R₁ ' is C₁₋₄ alkoxycarbonyl,phenoxycarbonyl or benzyloxycarbonyl, converting R₁ ' into R₁ ;optionally converting R₁, R₂ or R₃ in the resulting compound of formula(I) into another R₁, R₂ or R₃ ; and optionally forming an N-oxide orpharmaceutically acceptable salt thereof.

Preferred examples of the leaving group (L₉) include halo, such aschloro and bromo, and labile acyloxy, such as mesyloxy and tosyloxy.

The cyclisation may be carried out in a solvent in the presence of abase, as described hereinbefore for the reaction between compounds offormulae (X) and (XI).

The conversion of R₁ ', when C₁₋₄ alkoxycarbonyl phenoxycarbonyl orbenzyloxycarbonyl, into R₁, the optional conversion of R₁, R₂ or R₃ inthe resulting compound of formula (I) into another R₁, R₂ or R₃, and theoptional formation of an N-oxide or pharmaceutically acceptable salt maybe carried out as described hereinbefore.

The compound of formula (XIII) may be prepared by converting the hydroxymoiety in a compound of formula (XIV); ##STR15## wherein R₁ ', R₂, R₃, nand the configuration of the C_(a) and C_(b) hydrogen atoms are asdefined hereinbefore and one of X and Y is hydrogen and the other ishydroxyethyl, into a leaving group (L₉).

In the case of the aforementioned examples for the leaving group (L₉),the conversion may be carried out by reacting a compound of formula(XIV) with thionyl chloride, hydrogen bromide, mesyl or tosyl chloride.

The compound of formula (XIV) may in turn be prepared by reacting acompound of formula (X), as hereinbefore defined, with ethylene oxide ina solvent, such as ethanol, at, for example, room temperature. When R₁ 'is C₁₋₄ alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, thereaction occurs preferentially at the azepine nitrogen atom so that themajor resulting compound of formula (XIV) is that wherein X ishydroxyethyl and Y is hydrogen. When, on the other hand, R₁ ' is R₁, thereaction occurs preferentially at the nitrogen atom attached to R₁ sothat the major resulting compound of formula (XIV) is that wherein X ishydrogen and Y is hydroxyethyl.

The compounds of formulae (II) and (X) can both be prepared from acompound of formula (XV); ##STR16## wherein R₁ ', R₂, R₃, n, G and theconfiguration of the C_(a) and C_(b) hydrogen atoms are as definedhereinbefore; (i) in the case of a compound of formula (II), by reactionwith a compound of formula (XI), as defined hereinbefore, and, in thecase where s or u is 1, reducing the carbonyl moiety to a methylenemoiety; or (ii) in the case of a compound of formula (X), by cyclisationto form the azepine ring.

The reaction between the compounds of formulae (XV) and (XI) to give acompound of formula (II) may be carried out in a similar manner to thereaction between the compounds of formulae (X) and (XI), as describedhereinbefore. When either of the leaving groups (L₇ and L₈) in acompound of formula (XI) is halo and s or u is 1 when G in formula (XV)is CH₂ L₁, L₁ being hydroxy, there is a risk of a side-reaction betweenthe compound of formula (XI) and the hydroxymethyl substituent in thecompound of formula (XV). It is therefore preferred not to use thiscombination of variables, for example, by using a compound of formula(XI), wherein s and u are 0, or by using another value for the leavinggroup (L₇ or L₈) or the leaving group (L₁). Alternatively, thehydroxymethyl substituent may be protected using a standard method andthen the reaction with a compound of formula (XI) may be carried out andthe resulting compound deprotected using a standard method.

When s or u is 1, the preparation proceeds through an intermediate offormula (XVI); ##STR17## wherein R₁ ', R₂, R₃, n, G, the configurationof the C_(a) and C_(b) hydrogen atoms, s', t' and u' are as definedhereinbefore.

The reduction of the carbonyl moiety may be carried out in a similarmanner to the reduction of the carbonyl moiety in an intermediate offormula (XII) although it is possible that G, when formyl, carboxy or aC₁₋₄ alkyl ester thereof, may be reduced as a side-reaction. For such acombination of variables, therefore, it is preferred to use a selectivereducing agent that would minimise such side-reaction occurring, such asdiborane. Alternatively, as any reduction of formyl, carboxy or a C₁₋₄alkyl ester thereof would result mainly in a hydroxymethyl substituent,it may be desirable to allow the side-reaction to occur especially ashydroxymethyl is a favourable substituent for cyclisation. As a furtheralternative, the hydroxymethyl substituent may be oxidised back toformyl or carboxy using manganese dioxide or potassium permanganate and,if a C₁₋₄ alkyl ester were required, esterifying the carboxy group soformed.

The cyclisation of a compound of formula (XV) to give a compound offormula (X) may be carried out in a similar manner to the cyclisation ofa compound of formula (II).

The compound of formula (XV) may be prepared by reducing a compound offormula (XVII); ##STR18## wherein R₂ to R₄, n and the configuration ofthe C_(a) and C_(b) hydrogen atoms are as defined hereinbefore and R₁₁is C₁₋₄ alkyl; optionally converting the hydroxy group of thehydroxymethyl substituent in the resulting compound of formula (XVIII),##STR19## wherein R₂ to R₄, n and the configuration of the C_(a) andC_(b) hydrogen atoms are as defined hereinbefore, into another leavinggroup (L₁), or optionally oxidising the hydroxymethyl substituent toformyl or carboxy and optionally esterifying a carboxy group so formedinto a C₁₋₄ alkyl ester thereof; and optionally converting the C₁₋₄alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl group into R₁.

In order not to reduce the C₁₋₄ alkoxycarbonyl, phenoxycarbonyl orbenzyloxycarbonyl group, the reduction of a compound of formula (XVII)is preferably carried out with lithium aluminium hydride at a lowtemperature or with lithium triethylborohydride.

The optional conversion of the hydroxy group of the hydroxymethylsubstituent in the resulting compound of formula (XVIII) may be carriedout conventionally. For example, the optional conversion of the hydroxygroup into one of the other leaving groups (L₁), as definedhereinbefore, may be carried out with thionyl chloride (when L₁ ischloro), phosphorous tribromide (when L₁ is bromo), a C₁₋₄ alcohol andacid (when L₁ is C₁₋₄ alkoxy), mesyl or tosyl chloride (when L₁ is mesylor tosyl), a C₁₋₄ alkanoyl chloride or anhydride (when L₁ is C₁₋₄alkanoyloxy) and a C₁₋₄ alkoxycarbonyl chloride (when L₁ is C₁₋₄alkoxycarbonyloxy).

The optional oxidation of the hydroxymethyl substituent in a compound offormula (XVIII) into formyl, carboxy or a C₁₋₄ alkyl ester thereof maybe carried out by reaction with manganese dioxide (to give formyl), withpotassium permanganate (to give carboxy) or with a mixture of manganesedioxide, sodium cyanide, acetic acid and a C₁₋₄ alkanol (to give a C₁₋₄alkyl ester).

It is preferred however that no conversion of the hydroxy group or thehydroxymethyl substituent is carried out and that therefore the leavinggroup (L₁) is hydroxy.

The optional conversion of C₁₋₄ alkoxycarbonyl, phenoxycarbonyl orbenzyloxycarbonyl into R₁ may be carried out as described hereinbefore.In fact, in relation to the most preferred process of the presentinvention, namely the first process involving the cyclisation of acompound of formula (II), it is preferred that any such conversion iscarried out at this stage providing of course that the resulting group(R₁) is not likely to interfere with the course of any subsequentreaction or to be affected by it. If, however, either is likely, then itis preferred to maintain the C₁₋₄ alkoxycarbonyl, phenoxycarbonyl orbenzyloxycarbonyl group until after the subsequent reactions have beencarried out and then to carry out the required conversion. In thepreferred case when, in a compound of formula (XV), G is CH₂ L₁, L₁being hydroxy, and R₁ ' is R₁ is methyl, it is particularly advantageousto prepare such compounds by reducing both ester functions in thecorresponding compound of formula (XVII) in one operation. Thus, theCOOR₁₁ ester function becomes hydroxymethyl and the COOR₄ ester functionbecomes methyl. A convenient reducing agent for such a reduction islithium aluminium hydride, which is preferably used at room temperatureor above in a solvent, such as diethyl ether.

The compound of formula (XVII) may be prepared by reacting a compound offormula (XIX); ##STR20## wherein R₂ and R₁₁ are as defined hereinbefore,with a compound of formula (XX); ##STR21## wherein R₃, R₄ and n are asdefined hereinbefore.

The reaction between the compounds of formulae (XIX), when R₂ ishydrogen, and (XX) is preferably carried out with an excess of thecompound of formula (XIX) as solvent.

Alternatively although less preferred when R₂ is hydrogen, the compoundof formula (XV) may be prepared by reacting a compound of formula (XXI);##STR22## wherein R₂ is as defined hereinbefore and R₁₂ is hydrogen orC₁₋₄ alkyl, with a compound of formula (XX), as defined hereinbefore; inthe case when R₁₂ is hydrogen, optionally converting the hydroxy groupof the hydroxymethyl substituent in the resulting compound of formula(XVIII), as defined hereinbefore, into another leaving group (L₁), oroptionally oxidising the hydroxymethyl substituent to formyl or carboxyand optionally esterifying a carboxy group so formed into a C₁₋₄ alkylester thereof; and optionally converting the C₁₋₄ alkoxycarbonyl,phenoxycarbonyl or benzyloxycarbonyl into R₁.

The reaction between the compounds of formulae (XXI) and (XX) ispreferably carried out in a solvent, such as dimethylformamide, in thepresence of barium carbonate.

The compound of formula (XX) may be prepared by reacting a compound offormula (XXII); ##STR23## wherein R₃ and n are as defined hereinbefore,with a compound of formula (XXIII);

    Cl.sub.2 NCO.sub.2 R.sub.4                                 (XXIII)

wherein R₄ is as defined hereinbefore.

The reaction between the compounds of formulae (XXII) and (XXIII) ispreferably carried out in a solvent, such as toluene, at a temperatureof 25° to 75° C.

The compound of formula (XXIII) is preferably prepared in situ byreacting a mixture of chlorine and a compound of formula (XXIV);

    H.sub.2 NCO.sub.2 R.sub.4                                  (XXIV)

wherein R₄ is as defined hereinbefore.

The reaction between the compound of formula (XXIV) and chlorine ispreferably carried out in buffered aqueous solution.

The compounds of formulae (XIX), (XXI), (XXII) and (XXIV) are knowncompounds or can be prepared in a manner similar to the preparation ofknown compounds.

The intermediates of formulae (II), (III), (IV), (IX), (X), (XII),(XIII), (XIV), (XV), (XVI), (XVII), and (XVIII) are novel intermediatesand represent part of the present invention. Collectively they are offormulae (XXV) and (XXVI); ##STR24## wherein R₂, R₃, n and theconfiguration of the C_(a) and C_(b) hydrogen atoms are as definedhereinbefore and either Z is methylene and either R₁₃ is COOR₄ or R₁₀,R₄ and R₁₀ being as defined hereinbefore, and R₁₄ and R₁₅ together areC₁₋₃ alkylene, or R₁₃ is R₁ ', as defined hereinbefore, and R₁₄ and R₁₅are both hydrogen, or R₁₄ is W, as defined hereinbefore, and R₁₅ is V,as defined hereinbefore, or R₁₄ is Y, as defined hereinbefore, and R₁₅is X, as defined hereinbefore, or R₁₄ and R₁₅ together are (CO)_(s)'--(CH₂)_(t) '--(CO)_(u) ', s', t' and u' being as defined hereinbefore,or Z is J, as hereinbefore defined, R₁₃ is R₁ ', as hereinbeforedefined, and R₁₄ and R₁₅ together are C₁₋₃ alkylene; and ##STR25##wherein R₂, R₃, n and the configuration of the C_(a) and C_(b) hydrogenatoms are as defined hereinbefore and either R₁₆ is R₁ ', as definedhereinbefore, and R₁₇ and R₁₈ are both hydrogen or together are eitherC₁₋₃ alkylene or (CO)_(s) '--(CH)_(t) '--(CO)_(u) ', s', t' and u' beingas defined hereinbefore, and R₁₉ is G, as defined hereinbefore, or R₁₆is COOR₄, R₄ being as defined hereinbefore, R₁₇ and R₁₈ are bothhydrogen and R₁₉ is COOR₁₁, R₁₁ being as defined hereinbefore, orhydroxymethyl.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I), or an N-oxide or pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared bya mixture, is usually adapted for oral or parenteral administration and,as such, may be in the form of tablets, capsules, oral liquidpreparations, powders, granules, lozenges, reconstitutable powders, orinjectable or infusable solutions or suspensions. Orally administrablecompositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents,fillers, tabletting lubricants, disintegrants and acceptable wettingagents. The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention, or an N-oxide or pharmaceuticallyacceptable salt thereof and a sterile vehicle. The compound, dependingon the vehicle and concentration used, can be either suspended ordissolved in the vehicle. In preparing solutions, the compound can bedissolved for injection and filter sterilised before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are dissolved inthe vehicle. Parenteral suspensions are prepared in substantially thesame manner, except that the compound is suspended in the vehicleinstead of being dissolved and sterilised by exposure to ethylene oxidebefore suspension in a sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the compound.

The dose of the compound used in the treatment of CNS disorders, such asdepression or anxiety, will vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 10.0 mg.,for example 0.2 to 1 mg; and such unit doses may be administered morethan once a day, for example two or three times a day, so that the totaldaily dosage is in the range of about 0.01 to 10 mg/kg; and such therapymay extend for a number of weeks or months.

The invention also provides a method of treatment of CNS disorders, inparticular depression in mammals including humans, which comprisesadministering to the sufferer an anti-depressant effective amount of acompound of the invention, or an N-oxide or pharmaceutically acceptablesalt thereof.

The invention further provides a compound of the invention, or anN-oxide or pharmaceutically acceptable salt thereof, for use in thetreatment of CNS disorders in particular depression.

The following Examples illustrate the preparation of the compounds ofthe invention. The following Descriptions illustrate the preparation ofintermediates to the compounds of the present invention. Alltemperatures are in degrees celsius and 'Rec' means recrystallised from.

DESCRIPTION 1 trans-1-Chloro-2-ethoxycarbonylaminoindane (D1) ##STR26##

The title compound was prepared according to the procedure of B. J.Walker and P. J. Wrobel, J.C.S. Chem. Comm., 1980, 462 (85% yield; m.p.82°-84°).

DESCRIPTION 2trans-1-Chloro-2-ethoxycarbonylamino-1,2,3,4-tetrahydronaphthalene (D2)##STR27##

The title compound was prepared using a procedure similar to the oneemployed in Description 1 (74% yield; m.p. 124°-6°).

DESCRIPTION 3trans-1-(2-Hydroxymethylanilino)-2-ethoxycarbonylamino-1,2,3,4-tetrahydronaphthalene(D3) ##STR28##

A solution oftrans-1-chloro-2-ethoxycarbonylamino-1,2,3,4-tetrahydronaphthalene (12.8g; 0.05 moles) and o-aminobenzyl alcohol (6.2 g; 0.05 moles) in drydimethyl formamide (50 ml) was treated with finely ground bariumcarbonate (5.4 g; 0.0275 moles) and stirred under nitrogen at 85° for 10h. The reaction mixture was diluted with water and extracted into ether.The combined organic layers were washed exhaustively with water, dried(Na₂ SO₄) and concentrated in vacuo to give a light brown foam (15.6 g)which was purified on silica gel using 25% ethyl acetate in petroleumether 60/80 as eluant. Pooling of pure fractions produced the titlecompound as a colourless crystalline solid (6.1 g; 35%) m.p. 134°-5°(Rec. pentane/ether). Earlier fractions which were slightly contaminatedwith less polar impurity, afforded a further 1.4 g (8%) of the requiredproduct (m.p. 134°-5°) after recrystallisation from pentane/ether.

Nmr (CDCl₃): δ: 1.18 (3H,t,J=7), 1.5-2.5 (3H,m), 2.90 (2H,m), 4.04(2H,q,J=7), 4.15 (1H,m), 4.57 (2H,s), 4.75 (2H, overlapping doublets),6.65 (1H,m), 7.2 (6H,m).

DESCRIPTION 4trans-1-(2-Methoxycarbonylanilino)-2-ethoxycarbonylaminoindane (D4)##STR29##

trans-1-Chloro-2-ethoxycarbonylaminoindane (20 g, 0.084 moles) wastreated with methyl anthranilate (60 ml) and stirred under nitrogen at60° for 5 hr. The resulting viscous mixture was diluted with ether (500ml), washed exhaustively with 2.5N HCl (8×250 ml), and then withsaturated sodium bicarbonate followed by brine. After drying (Na₂ SO₄)and concentration in vacuo a brown solid (25.7 g) was obtained.Crystallisation from pentane/ether afforded the title compound (14 g;58%) m.p. 108°-110°. Concentration of mother liquors gave a less puresecond crop (2.6 g).

Nmr (CDCl₃) δ: 1.21 (3H,t,J=7), 2.30 (1H,dd,J=16,6) 3.42 (1H,dd,J=16,7),3.80 (3H,s), 3.9-4.5 (3H, m, overlapping signals), 4.92 (1H,d,J=5), 4.95(2H, m, overlapping signals), 6.65 (1H, m), 7.26 (6H, m), 7.94(1H,dd,J=9, 1.5).

DESCRIPTION 5trans-1-(2-Hydroxymethylanilino)-2-ethoxycarbonylaminoindane (D5)##STR30##

A solution of the ester D4 (1.0 g, 2.8 mmoles) in dry tetrahydrofuran (6ml) was cooled below -10° under nitrogen and treated dropwise withSuper-hydride (Lithium triethylborohydride) (10 ml of a 1MTetrahydrofuran solution). Stirring was continued overnight at roomtemperature. The reaction mixture was then cooled below 0° and treatedwith water (1 ml) followed by 5N HCl (25 ml). After stirring for 30mins. the mixture was diluted with pentane. The aqueous layer was washedwith ether (2×20 ml) basified (40% NaOH) and extracted into ether. Theorganic phase was washed (brine), dried (Na₂ SO₄) and concentrated invacuo to give the title compound as a colourless solid (0.75 g, 81%)m.p. 115°-7° (rec. ether/pentane).

Nmr (CDCl₃) δ: 1.17 (3H,t,J=7), 2.76 (1H,dd,J=16,8), 3.34(1H,dd,J=16,8), 4.02 (2H,q, J=7), 4.35 (1H,m), 4.62 (2H,s), 4.82(1H,d,J=7), 4.95 (1H,broad), 6.5-7.5 (8H,m).

DESCRIPTION 6trans-1-(4-Methoxy-2-hydroxymethylanilino)-2-ethoxycarbonylaminoindane(D6) ##STR31##

A solution of 2-amino-5-methoxybenzyl alcohol (5 g; 32.7 m. mol) andtrans-1-chloro-2-ethoxycarbonylaminoindane (7.83 g; 32.7 m.mol) indimethylformamide (80 ml) was treated with barium carbonate (3.37 g; 17m.mol) in a manner similar to that in Description 3 to give the titlecompound (5.1 g; 44%), m.p. 142°-144° (from ethyl acetate).

Nmr (CDCl₃) δ: 1.08(3H,t,CO₂ CH₂ CH₃); 2.40-3.45 (2H,dd, 2×CH);3.60(3H,s,OCH₃); 4.40(2H,s,CH₂ OH); 3.50-4.80(5H,m,CO₂ CH₂ +NHCH+OH);5.47 (1H, d,8 Hz;CH); 6.40-7.40(7H,m,aromatic CH).

DESCRIPTION 7trans-1-Ethoxycarbonylamino-1,2,11,11a-tetrahydro-6H-benzo[f]indeno[1,7-bc]azepine(D7) ##STR32##

The alcohol prepared in Description 5 (8.6 g; 0.026 moles) was dissolvedin methanesulphonic acid (86 g; 58 ml) and the cooled solution wastreated with phosphorus pentoxide (17.2 g) and stirred at roomtemperature for 4 days. The mixture was poured onto ice, neutralised topH7 (40% NaOH) and extracted into ether. The organic layers were washed(water), dried (Na₂ SO₄) and concentrated in vacuo to give a yellow foam(6.4 g) containing two faster running products on tlc (Rf values 0.77and 0.6-SiO₂ /petroleum ether/ether-3/1). The mixture was separated onsilica gel using 20% ethyl acetate in petroleum ether as eluant. Themore polar component corresponded to the title compound and was isolatedas a colourless crystalline solid (1.87 g; 23%).

Nmr (CDCl₃) δ: 1.28 (3H,t,J=7), 2,57 (1H,dd,J=16,10), 3.15(1H,dd,J=16,8), 3.63 (1H,d,J=15), 4,25 (5H, overlapping signals), 4.68(1H, d,J=8), 5.07 (1H, broad doublet), 6.5-7.3 (7H,m).

DESCRIPTION 8trans-1-Ethoxycarbonylamino-1,2,3,7,12,12a-hexahydrobenzo[f]naphth[1,8-bc]azepine(D8) ##STR33##

The title compound was prepared using a procedure analogous to the oneoutlined in Description 7 (21% yield).

Nmr (CDCl₃) δ: 1.25 (3H,t,J=7), 1.5-2.8 (2H,m), 2.85 (2H, m), 3.38(1H,d,J=15), 3.75-4.90 (4H, overlapping signals), 4.85 (1H,d,J=15), 4.95(1H,d,broad), 5.07 (1H,d,J=6), 6.35-7.4 (7H,m).

DESCRIPTION 9trans-1-Ethoxycarbonylamino-11-bromoacetyl-1,2,11,11a-tetrahydro-6H-benzo[f]indeno[1,7-bc]azepine(D9) ##STR34##

Bromoacetyl bromide (0.88 ml; 0.01 moles) was added dropwise to asolution of the amine prepared in Description 7 (3.08 g; 0.01 moles) indry methylene chloride (25 ml) containing finely ground potassiumcarbonate (2.76 g; 0.02 moles) and cooled to 0°. Stirring was continuedfor 27 hours and during this period a further portion (0.2 ml) ofbromoacetyl bromide was added. The mixture was then treated with waterand after separation of the organic phase the aqueous layer wasextracted with methylene chloride. The combined organic layers werewashed (water), dried, (Na₂ SO₄) and concentrated in vacuo to give ayellow solid. Purification by trituration with pentane/ether affordedthe title compound as a colourless crystalline solid (4.1 g; 95%) m.p.207.5°-210° C. (rec. ether).

Nmr (CDCl₃) δ: 1.33 (3H,t,J=7), 2.75 (1H,dd,H=15,10), 3.32(1H,dd,J=16,8), 3.44 (1H,d,J=13), 3.80 (2H,s), 4.2 (4H,overlappingsignals), 6.1 (2H,overlapping doublets) 6.8-7.5 (7H, m).

DESCRIPTION 10trans-1-Ethoxycarbonylamino-12-bromoacetyl-1,2,3,7,12,12a-hexahydrobenzo[f]napth[1,8-bc]azepine(D10) ##STR35##

The title compound was prepared using a procedure similar to the oneoutlined in Description 9 (77% yield).

Nmr (CDCl₃) δ: 1,30 (3H,t,J=7), 2.0 (2H,m), 2,80 (2H,m), 3,44(1H,d,J=14), 3,65 (1H,d,J=10), 3,72 (1H,d,J=10), 3,89 (1H,m), 4.19(2H,q,J=7), 4,53 (1H,d,J=14), 5,54 (1H,d,J=9), 5,97 (1H,d,J=10), 6,97(3H,m), 7,30 (4H,m).

DESCRIPTION 11trans-10-Oxo-1,10,11,12,12a,12b-Hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene-12-carboxylicacid ethyl ester (D11) ##STR36##

A solution of the urethane prepared in Description 9 (3.35 g; 7.8mmoles) in dry dimethyl formamide (200 ml) was added over a period of 30minutes to a stirred suspension of sodium hydride (0.26 g of 80%dispersion in oil; 8.6 mmoles) in the same dry solvent (20 ml) undernitrogen. Reaction temperature was maintained below 5° during additionand then allowed to rise to room temperature while stirring wascontinued for a further 3 h. The mixture was then carefully diluted withwater and extracted into ether. The organic phase was washedexhaustively with water, dried (Na₂ SO₄) and concentrated to give thetitle compound as a pale yellow solid (2.35 g; 90%) which was usedwithout further purification.

Nmr (CDCl₃) δ: 1.35 (3H,t,J=7), 2.75 (1H,dd,J=16,10), 3,50 (1H,d,J=14),3.55 (1H,dd,overlapping), 3.65-4.50 (4H,overlapping signals), 4.86(1H,d,J=16), 5.35 (1H,d,J=11), 6.80-7.40 (6H,m), 7.60 (1H,m).

DESCRIPTION 12trans-11-Oxo-1,2,6,11,12,13,13a,13b-octahydro-10b,13-diazabenzo[gh]pleiadene-13-carboxylicacid ethyl ester (D12) ##STR37##

The title compound was prepared using the method outlined in Description11 (yield 75%).

Nmr (CDCl₃) δ: 1.35 (3H,t,J=7), 2.85 (3H,m), 3.50 (2H,m), 3.80-4.50(5H,overlapping signals), 4.95 (1H,d,J=16), 5.33(1H,d,J=11), 6.80-7.40(7H,m).

DESCRIPTION 13trans-1,10,11,12,12a,12b-Hexahydro-5H-9b,12-diaza-benzo[5,6]cyclohepta[1,2,3,4-def]fluorene-12-carboxylicacid ethyl ester (D13) ##STR38##

A solution of the urethane prepared in Description 11 (2.2 g; 6.3mmoles) in dry tetrahydrofuran (15 ml) was added dropwise to 10.5 ml of1M diborane in tetrahydrofuran cooled to ice temperature under nitrogen.The solution was then refluxed for 2 hours. After cooling to -10° themixture was carefully acidified (5N HCl) and stirred for 30 mins.Solvent was removed in vacuo and the residue treated with 2N NaOH beforeextraction into ether. The dried (Na₂ SO₄) organic phase wasconcentrated in vacuo to give a foam (1.9 g). Purification on silica gelusing 15% ethyl acetate in petroleum ether 60/80 as eluant afforded thetitle compound as a colourless foam (1.45 g; 70%).

Nmr (CDCl₃) δ: 1.32 (3H,t,J=7), 3.0-4.7 (12H,m), 6.6-7.3 (7H,m).

DESCRIPTION 14trans-1,2,6,11,12,13,13a,13b-Octahydro-10b,13-diazabenzo[gh]pleiadene-13-carboxylicacid ethyl ester (D14) ##STR39##

The title compound was prepared using a method similar to the oneoutlined in Description 13.

Nmr (CDCl₃) δ: 1.20 (3H,t,J=7), 1.50-2.50 (2H,m), 2.75 (2H,m), 3.25-4,40(9H,m,overlapping signals), 4.52 (1H,d,J=13), 7.0 (7H,m).

DESCRIPTION 15trans-1-(4-Methoxy-2-hydroxymethylanilino)-2-methylaminoindane (D15)##STR40##

A solution of the carbamate prepared in Description 6 (4.00 g; 11.23m.mol) in dry tetrahydrofuran (20 ml) was added dropwise to a stirredsuspension of lithium aluminium hydride (1.0 g; 26.3 m.mol) in dry ether(10 ml), under a nitrogen atmosphere, at 0°. The mixture was allowed towarm to room temperature and stirring continued for 2 days. The excessof hydride was decomposed as described in Example Ia and work-up gave abrown gum (2.66 g). Chromatography on Kieselgel 60 (100 g) in ethylacetate containing increasing amounts of methanol gave the titlecompound as a pale gum (1.086 g; 33%).

Nmr (CDCl₃) δ: 2.37(3H,s,NCH₃); 2.50-3.90(6H,br,CH₂ +CH+2×NH+OH);3.64(3H,s,OCH₃); 4.47(2H,s,CH₂ OH); 4.50-4.78(1H,d,CH); 6.54-6.85 and7.05-7.30 (7H,m,aromatic CH).

DESCRIPTION 16trans-4-(4-Methoxy-2-hydroxymethylphenyl)-1-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[1,2-b]pyrazine(D16) ##STR41##

A solution of the diamine prepared in Description 15 (880 mg; 2.95m.mol) and dry triethylamine (2 ml) in dibromoethane (6 ml) was addeddropwise, over 30 min, to dibromoethane (10 ml) at 100° with stirring,under a nitrogen atmosphere. After 1 hr, triethylamine (2 ml) was addedand stirring continued for a further 1 hr at 100°. The mixture wasallowed to cool to room temperature and then partitioned between dilutesodium hydroxide (200 ml) and chloroform (200 ml). The organic phase waswashed with water (2×100 ml), saturated brine (50 ml) and dried (K₂CO₃). Evaporation in vacuo gave a buff solid (0.8 g) which wasrecrystallised from chloroform-ether to give the title compound asoff-white crystals (478 mg; 50%), m.p. 179°-183°.

Nmr (CDCl₃): δ: 2.35-3.25 (8H,m,3×CH₂ +CH+OH), 2.40 (3H,s,NCH₃),3.83(3H,s,OCH₃), 4.20(1H,d J9 Hz,CH), 4.50-5.00(2H,ABq, J13 Hz,CH₂ OH),6.15(1H,dJ8 Hz,CH), 6.75-7.45 (6H,m,aromatic).

DESCRIPTION 17 trans-1-(2-Hydroxymethylanilino)-2-methylaminoindane(D17) ##STR42##

A solution of trans1-(2-methoxycarbonylanilino)-2-ethoxycarbonylaminoindane (1.73 kg; 4.9moles) in diethyl ether (36 l) was added dropwise to a suspension oflithium aluminium hydride (900 g; 23.7 moles) in diethyl ether (28 l),under nitrogen, over a period of ca 1.5 h. After stirring overnight atroom temperature the excess lithium aluminium hydride was carefullydecomposed with water (2.5 l), and 10% sodium hydroxide (30 l) and water(5 l) was added. The organic layer was separated and the aqueous phaseextracted with two further portions of ether (2×20 l). The combinedextracts were washed (water), dried (MgSO₄) and concentrated.Crystallisation from ethyl acetate/pet. ether afforded the titlecompound (1.17 Kg; 89%) m.p. 113°-4°.

Nmr (CDCl₃) δ: 2.2 (2H, brs, exchanges with D₂ O), 2.45 (3H,s), 2.5-3.5(3H, overlapping signals), 4.6 (2H,s), 4.8 (1H, t, J=8), 5.07 (1H, d,J=8, exchanges with D₂ O), 6.5-7.5 (8H,m).

DESCRIPTION 18trans-4-(5-Chloro-2-hydroxymethylphenyl)-1-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[1,2-b]pyrazine(D18) ##STR43##

The title compound was prepared in a manner similar to that inDescription 16.

Nmr (CDCl₃) δ: 2.35 (3H,s,NCH₃), 2.40-3.40 (7H, overlapping signals),4.18 (1H,d,J9 Hz), 4.40-5.00 (2H, ABq, J13 Hz, CH₂ OH) 6.10 (1H,d, J7Hz, aromatic CH) 6.60-7.40 (6H,m,aromatic CH).

DESCRIPTION 19trans-4-(2-Hydroxymethyl-4-methylphenyl)-1-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[1,2-b]pyrazine(D19) ##STR44##

The title compound was prepared in a manner similar to that inDescription 16.

Nmr (CDCl₃) δ: 2.34 and 2.38 (2×3H,s, 2×CH₃), 2.30-3.25 (7H,overlappingsignals), 4.17 (1H,d,J9 Hz, CH), 4.25-5.20 (3H,m,CH₂ OH), 6.10 (1H,d, J7Hz, aromatic CH), 6.53-7.25 (6H,m, aromatic CH).

DESCRIPTION 20trans-4-(2-Hydroxymethylphenyl)-1-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[1,2-b]pyrazine(D20) ##STR45##

A solution of trans 1-(2-hydroxymethylanilino)-2-methylaminoindane (1.16kg; 4.3 moles) in 1,2-dibromoethane (7 l, 17.1 moles) and triethylamine(2.5 l; 34 moles) was added dropwise to stirred 1,2-dibromoethane (13 l;31.9 moles) at ca. 100° over a period of 1.5 h. This was followed bytriethylamine (2.5 l; 34 moles) added dropwise over 30 min. The reactionwas cooled to 50° and diethyl ether (80 l) was added with good stirring.After stirring for 1 h the precipitated triethylammonium bromide wasfiltered off and the resulting solution concentrated in vacuo to ca 3.5l. Addition of ethyl acetate (2.5 l) assisted crystallisation of therequired product. Filtration and trituration (pet. ether) afforded thetitle compound as a white crystalline solid (687 g; 54%) m.p. 166-7°.

Nmr (CDCl₃) δ: 2.3-3.4 (10H, overlapping signals), 4.3 (1H,d,J=9), 4.62(1H,d,J=13), 4.9 (1H,brs, exchange with D₂ O), 5.0 (1H,d,J=13), 6.15(1H,d,J=8), 6.7-7.6(7H,m).

DESCRIPTION 21trans-1-Methylamino-1,2,11,11a-tetrahydro-6H-benzo[f]indeno[1,7-bc]azepine(D21) ##STR46##

A solution of the product of Description 7 (1.16 g; 3.76 mmoles) in drytetrahydrofuran (20 ml) was added to a stirred suspension of lithiumaluminium hydride (0.42 g; 11.0 mmoles) in the same dry solvent (20 ml)under nitrogen. The mixture was refluxed for 1 h. After treatment withwet ether followed by careful addition of water the precipitate wasfiltered off and the filtrate concentrated to give the title compound asa dark oil (0.80 g; 85%). Maleate salt m.p. 182°-4° (Rec.acetone/ether).

Nmr (CDCl₃) δ: 2.2-2.7 (2H, m, overlapping signals), 2.6 (3H, s),3.0-3.5 (2H, m), 3.75 (1H, d, J=16), 4.3 (1H, d, J=16), 4.50 (1H, d,J=9), 6.6-7.3 (7H, m).

DESCRIPTION 22trans-1-Methylamino-1,2,3,7,12,12a-hexahydrobenzo[f]naphth[1,8-bc]azepine(D22) ##STR47##

A solution of the product of Description 8 (644 mg; 2.0 mmoles) in drydimethylformamide (4 ml) was added dropwise to a suspension of sodiumhydride (66 mg of an 80% dispersion in oil; 2.2 mmoles) in the same drysolvent (1 ml) cooled to 0° under nitrogen. After 12 min methyl iodide(0.14 ml; 2.2 mmoles) was added and the mixture was stirred for afurther 30 min. The reaction was then diluted with water and extractedinto ether. The organic phase was washed exhaustively with water, dried(Na₂ SO₄) and concentrated to givetrans-1-(N-ethoxycarbonyl-N-methylamino)-1,2,3,7,12,12a-hexahydrobenzo[f]napth[1,8-bc]azepineas a yellow foam (0.64 g; 96%). A solution of this product (0.57 g; 1.7mmoles) in ethanol (25 ml) was treated with sodium hydroxide (8 ml of a40% aqueous solution) and the mixture refluxed under nitrogen for 26 h.Solvent was removed in vacuo and the residue was diluted with water andextracted into ether. Further purification by extraction into 2N HClfollowed by neutralisation and back extractions into ether afforded thetitle compound as a yellow gum (0.30 g; 67%) which crystallised onstanding.

Nmr (CDCl₃) δ: 1.5-2.8 (2H,m), 2.55 (3H,s), 2.75 (5H,m), 3.40(1H,d,J=15), 4.82 (1H,d,J=15), 4.96 (1H,d,J=5), 6.3-7.3 (7H,m).Treatment with D₂ O resulted in exchange of two protons in the multipletat δ3.75.

EXAMPLE Iatrans-12-Methyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(E1) ##STR48##

A solution of the urethane prepared in Description 13 (1.4 g; 4.0mmoles) in dry tetrahydrofuran (10 ml) was added dropwise to a stirredsuspension of lithium aluminium hydride (0.45 g; 12.0 mmoles) in thesame dry solvent (4 ml) under nitrogen, and the mixture was refluxed for50 mins. Excess hydride was destroyed with wet ether and after carefultreatment with water the precipitate of aluminium oxides was filteredoff and the filtrate concentrated in vacuo to give the title compound asa light yellow foam (0.98 g; 89%) which crystallised on addition ofacetone.m.p. 151°-2° (from pentane/ethyl acetate).

Nmr δ: 2.20 (1H,ddd,J=10,10,6), 2.35 (3H,s), 2.50 (1H,ddd,J=12,12,3),2.61 (1H,dd,J=14,11), 2.87 (1H,m), 2.88 (1H,dd,J=14,6), 3.45(1H,d,J=13), 3.69 (1H,ddd,J=14.5,11,3), 3.87 (1H,ddd,J=14,3,3), 4.37(1H,d,J=13), 4.48 (1H,d,J=10), 6.7-7.3 (7H,m).

Treatment of the free base with 1 equivalent of maleic acid in acetonesolution afforded the maleate salt. m.p. 183°-5° (from acetone/ether).

    ______________________________________                                                      C        H      N                                               ______________________________________                                        Found           70.32      6.25   7.01                                        C.sub.23 H.sub.24 N.sub.2 O.sub.4 Requires                                                    70.39      6.16   7.14                                        ______________________________________                                    

EXAMPLE Ib (Alternative Procedure) ##STR49##

trans-4-(2-Hydroxymethylphenyl)-1-methyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[1,2-b]pyrazine(680 g; 2.31 moles) was added to stirring orthophosphoric acid (6.8 l ofan 88% solution) at ca 90°. After 1 h the mixture was poured onto amixture of ice (20 kg) and chloroform (12.5 l) and stirred vigorously as40% sodium hydroxide solution was carefully added to neutralise the acidwhile the temperature was maintained below 45°. The organic layer wasseparated and the aqueous phase extracted with two further portions ofchloroform. The combined chloroform layers were washed (water), dried(MgSO₄) and concentrated in vacuo. Purification by flash chromatography,using pet. ether/acetone (70/30) as eluant, followed by crystallisationafforded the title compound as a colourless solid (560 g; 88%). m.p.151°-2° (Rec twice pentane/ethyl acetate).

    ______________________________________                                                    C         H      N                                                ______________________________________                                        Found         82.43       7.27   10.30                                        C.sub.19 H.sub.20 N.sub.2 Requires                                                          82.57       7.29   10.13                                        ______________________________________                                    

EXAMPLE IItrans-13-methyl-1,2,6,11,12,13,13a,13b-octahydro-10b,13-diazabenzo[gh]pleiadene(EII) ##STR50##

Title compound was prepared from the urethane of Description 14 in amanner analogous to the procedure outlined in Example 1a.

Nmr (CDCl₃) δ: 1.50-4.0 (14H overlapping signals) 4.90 (1H,d,J=13), 7.1(7H,m).

Maleate Salt--m.p. 116°-7°.

    ______________________________________                                                      C        H      N                                               ______________________________________                                        Found           70.49      6.45   6.72                                        C.sub.24 H.sub.26 N.sub.2 O.sub.4 Requires:                                                   70.92      6.45   6.89                                        ______________________________________                                    

EXAMPLE IIItrans-7-Methoxy-12-methyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EIII) ##STR51##

The alcohol prepared in Description 16 (450 mg; 1.39 m.mol) inorthophosphoric acid (6 ml) was stirred at 95° for 8 h and then allowedto cool to room temperature. The mixture was poured into water (200 ml),basified with 40% sodium hydroxide solution and extracted withchloroform (2×150 ml). The combined extracts were dried (K₂ CO₃) andevaporation in vacuo gave a brown gum. Chromatography on Kieselgel 60(10 g) in 10% methanol-ethyl acetate gave the title compound as a gum(276 mg, 65%), which solidified on standing.

Nmr (CDCl₃) δ: 2.36(3H,s,NCH₃), 3.45(1H,d,J13 Hz,bridgehead CH), 3.74(3H,s,OCH₃), 4.33(1H,d,J13 Hz,bridgehead CH).

A portion (250 mg) of the above was converted into a monomaleate salt(200 mg), m.p. 208.5°-210° (from methanol-ether).

    ______________________________________                                                      C        H      N                                               ______________________________________                                        Found:          68.03      6.16   6.70                                        C.sub.24 H.sub.26 N.sub.2 O.sub.5 Requires:                                                   68.23      6.20   6.63                                        ______________________________________                                    

EXAMPLE IVtrans-7,12-Dimethyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EIV) ##STR52##

The title compound was prepared from the alcohol of Description 19 in asimilar manner to Example III and converted into a maleate salt m.p.207°-211° (dec) (from acetone).

    ______________________________________                                                      C        H      N                                               ______________________________________                                        Found           70.45      6.32   6.84                                        C.sub.24 H.sub.26 N.sub.2 O.sub.4 Requres:                                                    70.92      6.45   6.89                                        ______________________________________                                    

Nmr (d₆ DMSO) δ: 2.18 (3H,s,CH₃), 2.85 (3H,s,NCH₃), 6.97 and 7.15(2×3H,s,aromatic CH).

EXAMPLE Vtrans-8-Chloro-12-methyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EV) ##STR53##

The title compound was prepared from the alcohol of Description 18 in asimilar manner to Example III.

Nmr (CDCl₃) δ: 2.30-3.10 (6H, overlapping signals), 2.34 (3H,s,NCH₃),3.37 (1H,d,J14 Hz, bridgehead CH), 3.53-3.85 (1H,m,CH), 4.26 (1H,d,J14Hz, bridgehead CH), 4.45 (1H,d,J9 Hz,CH), 6.50-7.15 (6H,m,aromatic CH).

Found M⁺ : 310.1242.

C₁₉ H₁₉ N₂ Cl requires 310.1237.

A portion of the title compound was converted into a maleate salt, m.p.195°-197° (from acetone).

EXAMPLE VItrans-7-Hydroxy-12-methyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EVI) ##STR54##

A solution of the methoxy compound prepared in Example III (10 mg; 0.033mmoles) in 47% aqueous hydrobromic acid (1 ml) was heated under refluxfor 5 hr and then allowed to cool to room temperature. The mixture wasdiluted with water (20 ml), made basic (pH about 14) with 40% sodiumhydroxide solution and extracted with chloroform. The pH of the aqueouslayer was adjusted to 7 with conc. hydrochloric acid and extraction withchloroform (2×20 ml) removed the product. The extracts were dried(MgSO₄) and evaporation in vacuo gave a brown gum which was fractionatedby preparative layer chromatography on silica using 10% methanol-ethylacetate to develop the plates. The band at Rf 0.47 afforded the titlecompound as a pale yellow gum (3 mg; 32%) which solidified on standing.

Nmr (CDCl₃) δ: 2.00-3.00 (6H,m,(CH₂)₂ +CH+OH); 2.35 (3H,s,NCH₃);3.43(1H,d,J14 Hz, CH bridgehead); 3.55-3.80(2H,m,CH₂); 4.15-4.45(2H,m,CHbridgehead+NCH); 6.55-7.15 (6H,m, aromatic)

Found M⁺ 292.1572.

C₁₉ H₂₀ N₂ O requires 292.1576.

EXAMPLE VIItrans-1,10,11,12,12a,12b-Hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EVII) ##STR55##

The product obtained in Example I (13.8 g; 0.05 moles) in dry toluene(150 ml) was treated with ethyl chloroformate (48 ml, 0.50 moles) andthe mixture refluxed for 7 h. After concentration in vacuo excessreagent was removed by azeotropic distillation with several portions oftoluene. The residue was partitioned between water and ether, and theaqueous layer extracted with two further portions of ether. The combinedorganic layers were washed (brine), dried (Na₂ SO₄) and concentrated togive a crude foam (17 g) containing the requiredtrans-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene-12-carboxylicacid ethyl ester. A solution of this product in ethanol (300 ml) wastreated with sodium hydroxide (50 ml of a 40% aqueous solution) andrefluxed under nitrogen for 6 h. After concentration in vacuo thereaction mixture was diluted with water and extracted into ether. Theorganic phase was washed (brine), dried (Na₂ SO₄) and concentrated to adark foam. Chromatographic separation on silica using 30% methanol inethyl acetate as eluant afforded the title compound as an off-whitesolid (3.8 g; 30%) m.p. 132.5°-135° (Rec. ethyl acetate/petroleum ether60/80).

Nmr (CDCl₃) δ: 2.5-4.0 (9H,m,overlapping signals), 4.32 (1H,d,J=13),4.39 (1H,d,J=10), 6.6-7.3 (7H,m).

    ______________________________________                                                    C         H      N                                                ______________________________________                                        Found         82.38       6.92   10.53                                        C.sub.18 H.sub.18 N.sub.2 Requires                                                          82.41       6.92   10.67                                        ______________________________________                                    

EXAMPLE VIIItrans-12-Benzyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EVIII) ##STR56##

A solution of the product of Example VII (500 mg; 1.90 m moles) inacetone (25 ml) containing benzyl bromide (0.25 ml; 2.1 m moles) andpotassium carbonate (290 mg; 2.1 m moles) was stirred at roomtemperature for 6 h. After concentration in vacuo the residue wastreated with water and extracted into ether. The organic phase waswashed (brine), dried (Na₂ SO₄) and concentrated. Purification on silicagel using ethyl acetate as eluant afforded the title compound as acolourless solid (0.55 g; 82%).

Nmr (CDCl₃) δ: 2.1-3.0 (5H,m,overlapping signals), 3.16 (1H, d, J=13),3.45 (1H, d, J=13), 3.7 (2H, m, overlapping signals), 4.0 (1H, d, J=13),4.2-4.65 (2H, overlapping doublets), 6.6-7.6 (12H,m).

Treatment of the free base with one equivalent of maleic acid in acetonesolution afforded the maleate salt. m.p. 212°-5° (dec) (Rec. acetone).

EXAMPLE IXtrans-12-(Prop-2-enyl)-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diaza-benzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EIX) ##STR57##

The title compound was prepared by treatment oftrans-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorenewith allyl bromide using a procedure similar to the one outlined inExample VIII. Maleate salt m.p. 187°-190° (dec).

Nmr (CDCl₃) δ: 2.1-3.1 (6H,m), 3.45 (1H,d,J=13), 3.55-3.90 (3H,m), 4.4(1H,d,J=13), 4.5 (1H,d,J=9), 5.25-5.35 (2H,m), 5.75-6.25 (1H,m),6.65-7.35 (7H,m).

EXAMPLE Xtrans-12-(Prop-2-ynyl)-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo-[5,6]cyclohepta[1,2,3,4-def]fluorene(EX) ##STR58##

The title compound was prepared by treatment oftrans-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene with propargyl bromideusing a procedure similar to one outlined in Example VIII. Maleate saltm.p. 165°-70°.

Nmr (CDCl₃) δ: 2.0-2.95 (6H,m), 3.35-3.90 (5H,m), 4.35 (1H,d,J=14), 4.50(1H,d,J=8), 6.65-7.25 (7H,m).

EXAMPLE XI trans-12-(2-Hydroxyethyl)-1,10,11,12,12a,12b-hexahydro5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene (EXI) ##STR59##

A solution of the product of Example VII (0.5 g; 1.90 m moles) inmethanol (30 ml) containing potassium carbonate (0.26 g; 1.90 m moles)was treated with ethylene oxide as a gas for several minutes, andstirred overnight at room temperature. After concentration in vacuo, theresidue was treated with water and extracted into ether. The organicphase was dried (Na₂ SO₄) and solvent removed in vacuo. Purification onsilica gel using diethyl ether as eluant, progressively increasing thepolarity by adding up to 30% ethyl acetate, afforded the title compoundas a cream solid (0.35 g; 60%).

Nmr (CDCl₃) δ: 2.0-3.1 (8H, m), 3.45 (1H,d,J=14), 3.6-3.85 (4H,m), 4.35(1H,d,J=14), 4.45 (1H,d,J=10), 6.7-7.4 (7H,m).

Treatment of the free base with 1 equivalent of maleic acid in acetonegave the maleate salt, m.p. 175°-7°.

    ______________________________________                                        Analysis                                                                                    C        H      N                                               ______________________________________                                        Found:          68.13      6.14   6.69                                        C.sub.20 H.sub.22 N.sub.2 O Requires:                                                         68.23      6.20   6.63                                        ______________________________________                                    

EXAMPLE XIItrans-12-(2-Methoxyethyl)-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EXII) ##STR60##

A solution of the product of Example VII (0.5 g; 190 m moles) inpyridine (3 ml) was cooled in an ice bath and treated with methoxyacetylchloride (0.4 ml; 4.38 m moles). After stirring at room temperature for0.5 h the reaction mixture was treated with water and extracted intoether. The organic phase was washed once with 1M hydrochloric acid,dried (Na₂ SO₄), and concentrated in vacuo. Purification on silica gelusing diethyl ether as eluant afforded the requiredtrans-12-(methoxyacetyl)-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene as a brown solid (0.35 g; 55%). A solution of this compound(0.35 g; 1.05 m moles) in dry tetrahydrofuran (15 ml) was added dropwiseto a stirred suspension of lithium aluminium hydride (0.125 g; 3.2 mmoles) in the same dry solvent (5 ml) under nitrogen, and the mixturewas refluxed for 3 h. Excess hydride was destroyed with wet ether and,after careful treatment with water, the precipitate of aluminium oxideswas filtered off and the filtrate concentrated in vacuo. Purification onsilica gel using 50% ethyl acetate in diethyl ether as eluant affordedthe title compound as a brown oil (0.26 g; 78%).

Nmr (CDCl₃) δ: 2.1-3.1 (7H,m), 3.35 (3H,s), 3.45-3.95 (5H,m), 4.33(1H,d,J=14), 4.48 (1H,d,J=10), 6.6-7.3 (7H,m).

Treatment of the free base with 1 equivalent of maleic acid in acetonesolution gave the maleate salt, m.p. 170°-2°.

EXAMPLE XIIItrans-12-Ethyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EXIII) ##STR61##

A solution of the product of Example VII (0.5 g; 1.90 m moles) in drydichloromethane (8 ml) was cooled in an ice-bath and treated with aceticanhydride (0.233 g; 2.3 m moles) in one portion. After stirring at roomtemperature for 0.5 h the reaction mixture was treated with water andextracted into dichloromethane. The organic phase was dried (Na₂ SO₄)and solvent removed in vacuo. Purification on silica gel using diethylether as eluant afforded the requiredtrans-12-acetyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluoreneas a white solid (0.54 g; 93%).

This compound was reduced according to the method of Example XII, togive the title compound and the maleate salt prepared similarly, m.p.188°-9° (dec.).

Nmr (CDCl₃) δ: 1.15 (3H,t,J=8), 2.05-3.10 (7H, m, overlapping peaks),3.45 (1H,d,J=14), 3.60-4.05 (2H,m), 4.375 (1H,d,J=14), 4.50 (1H,d,J=8),6.65-7.35 (7H, m, overlapping peaks).

EXAMPLE XIVtrans-12-Cyclohexylmethyl-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EXIV) ##STR62##

The title compound was prepared according to the method of Example XII.Maleate salt m.p. 197°-9° (dec.).

Nmr (CDCl₃) δ: 0.65-3.0 (18H,m, overlapping signals), 3.6-3.9 (3H,m),4.3 (1H,d,J=14), 4.4 (1H,d,J=10), 6.6-7.4 (7H,m).

EXAMPLE XVtrans-12-(3-Oxobutyl)-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EXV) ##STR63##

A solution of the product of Example VII (0.5 g; 1.90 m moles) in1,4-dioxan (40 ml) was treated with methyl vinyl ketone (0.23 ml; 2.8 mmol) and stirred at 100° under nitrogen for 15 h. Concentration in vacuofollowed by purification of the residue on silica gel using 50% ethylacetate 60°-80° petroleum ether afforded the title compound as a beigesolid (0.48 g; 76%).

Nmr (CDCl₃) δ: 2.20 (3H,s), 2.40-3.00 (9H,m, overlapping signals), 3.42(1H,d,J=14), 3.50-3.80 (2H,m), 4.33 (1H,d,J=14), 4.44 (1H,d,J=10),6.75-7.25 (7H,m).

Treatment of the free base with 1 equivalent of maleic acid in acetonegave the maleate salt, m.p. 148°-50°.

EXAMPLE XVItrans-12-(2-Ethoxycarbonylethyl)-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EXVI) ##STR64##

The title compound was prepared from ethyl acrylate according to themethod of Example XV. Maleate salt m.p. 178°-183° (dec).

Nmr (CDCl₃) δ: 1.28 (3H,t,J=8), 2.1-3.2 (9H,m, overlapping signals),3.30-3.85 (3H,m), 3.90-4.50 (4H,m), 6.65-7.25 (7H,m).

EXAMPLE XVII trans-12-(2¹-dimethylaminoethyl)-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene(EXVII) ##STR65##

A solution of the product of Example VII (0.50 g; 1.91 mmoles) in drymethylene chloride (10 ml) containing anhydrous potassium carbonate(0.29 g) was cooled in ice and treated dropwise with bromoacetyl bromide(0.183 ml; 2.1 mmoles). The reaction was allowed to warm to roomtemperature. After 1 h the reaction mixture was diluted with methylenechloride and washed with water. Drying (Na₂ SO₄) followed byconcentration in vacuo affordedtrans-12-(bromoacetyl)-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluoreneas a light brown foam (0.73 g). This material was dissolved in a mixtureof ethanol (50 ml) and 1,4-dioxan (25 ml) and treated with dimethylamine(5 ml of 33% w/w solution in industrial methylated spirits). After 0.5 hthe solvent was removed in vacuo, and trituration of the residue withether afforded an off white solid characterised astrans-12-(dimethylaminoacetyl)-1,10,11,12,12a,12b-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene.Refluxing this product in dry tetrahydrofuran (100 ml) with lithiumaluminium hydride (0.21 g; 5.7 mmoles) for 2 h afforded the titlecompound as a light brown oil (0.45 g; 70%).

Nmr (CDCl₃) δ: 2.30 (6H,s), 2.30-3.15 (9H,m, overlapping signals), 3.43(1H,d,J=13), 3.55-3.90 (2H,m), 4.35 (1H,d,J=13), 4.50 (1H,d,J=9),6.6-7.3 (7H,m).

PHARMACOLOGY

Compounds of the invention inhibit the behavioural symptoms induced by5-methoxy-N,N-dimethyltryptamine (5-MDMT), a central 5-hydroxytryptamineagonist, and are central 5HT antagonists. As such they would be expectedto possess antidepressant (Ogren, S O, Fuxe, K, Agnati, L F, GustafssonJ A, Jonsson, G, and Holm A C, 1979, J Neural Trans, 46, 85-103) and/oranxiolytic (Stein, L, Kline, D, and Bellugi, J D, 1975, in Advances inBiochemical Psychopharmacology, ed Costa, E, and Greengard, P, Vol 14,29-44, Raven Press, NY) activity.

METHOD

Mice (♂CD-1 Charles River) are pretreated with the compounds (10animals/group) under investigation and 1 h later are injected with 10mg/kg i.p. 5-methoxy-N,N-dimethyltryptamine (Sigma). The symptoms offore-paw tapping movements, head jerks and splayed limbs are scored: 1,present; 0, absent, giving a maximum score of 3/mouse or 30/group.Results are expressed as the percentage inhibition compared to the grouptreated with 5-methoxy-N,N-dimethyltryptamine alone. The dose ofcompound inhibiting the symptoms by 50% is determined graphically. Theresults are shown in Table 1.

TOXICITY

No toxic effects were observed in the above tests.

                  TABLE 1                                                         ______________________________________                                        Compound             ED.sub.50 mg/kg (p.o.)                                   ______________________________________                                        trans-12-Methyl-1,10,11,12,12a,12b,-                                                               8                                                        hexahydro-5H--9b,12-diazabenzo[5,6]                                           cyclohepta[1,2,3,4,-def]fluorene                                              (Example 1)                                                                   ______________________________________                                    

BIOCHEMISTRY

Blockade of presynaptic α₂ -adrenoceptors on noradrenegic neuroneseffects an increase in intrasynaptic noradrenaline, and thus in thecentral nervous system could be expected to have an antidepressanteffect.

[³ H]-Clonidine binds to α₂ -adrenoceptor sites and inhibition of thisbinding correlates with the blockade of α₂ -adrenoceptors. In vitroinhibition by some of the present compounds of the binding of [³H]-clonidine to isolated rat-brain synaptic membrane fragments wastherefore determined to provide an indication of antidepressantactivity. This was carried out using standard biochemical binding studytechniques, by the method of Maggi et al, Eur. J. Pharm. 1980, 61, 91.IC₅₀ values were obtained from log [dose] against % inhibition curves;Ki values were determined using the Cheng-Prusoff equation. The resultsare shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound              Ki (nm)                                                 ______________________________________                                        trans-12-Methyl-1,10,11,12,12a,12b-                                                                  88                                                     hexahydro-5H--9b,12-diazabenzo[5,6]                                           cyclohepta[1,2,3,4-def]fluorene                                               (Example I)                                                                   trans-13-Methyl-1,2,6,11,12,13,13a,                                                                 169                                                     13b-octahydro-10b,13-diazabenzo                                               [gh]pleiadene (Example II)                                                    ______________________________________                                    

What we claim is:
 1. A compound of formula (XXV): ##STR66## wherein R₂and R₃ are the same or different and are hydrogen, hydroxy, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ alkylthio, halogen, or trifluoromethyl, and n is 1 or2, the hydrogen atom bonded to the C_(a) carbon atom being trans to thehydrogen atom bonded to the C_(b) carbon atom and either:(I) Z ismethylene; andR₁₃ is COOR₄ or R₁₀, R₄ being C₁₋₄ alkyl, phenyl or benzyland R₁₀ being C₁₋₄ alkyl substituted by halogen or halocarbonyl or, C₁₋₄alkylcarbonyl, C₃₋₇ cycloalkylcarbonyl, C₃₋₇ cycloalkyl C₁₋₃alkylcarbonyl or halo C₁₋₄ alkylcarbonyl, and R₁₄ and R₁₅ together areC₁₋₃ alkylene, or R₁₃ is hydrogen, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl or C₁₋₄ alkyl substituted by C₂₋₇ alkenyl, C₂₋₇ alkynyl,C₃₋₇ cycloalkyl, hydroxy, thiol, C₁₋₄ alkoxy, C₁₋₄ alkylthio, carboxy,C₁₋₄ alkoxycarbonyl, C₁₋₄ alkanoyl, amino optionally substituted by oneor two C₁₋₄ alkyl or by C₄₋₆ polymethylene optionally containing anoxygen or nitrogen atom, amino carbonyl optionally N-substituted by oneor two C₁₋₄ alkyl, or benzoyl or phenyl either being optionallyring-substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or trifluoromethylor C₁₋₄ alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, and R₁₄and R₁₅ are both hydrogen, or R₁₄ is W and R₁₅ is V, wherein one of Vand W is hydrogen and the other is (CH₂) L₉, L₉ being a leaving group,or one of R₁₄ and R₁₅ is hydrogen and the other is hydroxylethyl, or R₁₄and R₁₅ together are (CO)_(s') --(CH.sub. 2)_(t') --(CO)_(u'), whereins' and u' are 0 and t' is 0 to 3 such that s'+t'+u' is 1 to 3, withproviso that at least one of s' and u' is 1; or (II) Z is CO or CHOH;andR₁₃ is as defined above, and R₁₄ and R₁₅ together are C₁₋₃ alkylene.2. A compound according to claim 1, selected from the group consistingof:trans-1-ethoxycarbonylamino-1,2,11,11a-tetrahydro-6H-benzo[f]indeno[1,7-bc]azepine;trans-1-ethoxycarbonylamino-1,2,3,7,12,12a-hexahydrobenzo[f]naphth[1,8-bc]azepine;trans-10-oxo-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene-12-carboxylicacid ethyl ester; trans-11-oxo-1,2,6,11,12,13,13a, 13b-octahydro-10b,13-diazabenzo[gh]pleiadene-13-carboxylic acid ethyl ester;trans-1,10,11,12,12a,12b-hexahydro-5H-9b,12-diazabenzo[5,6]cyclohepta[1,2,3,4-def]fluorene-12-carboxylic acidethyl ester;trans-1,2,6,11,12,13,13a,13b-octahydro-10b,13-diazabenzo[gh]pleiadene-13-carboxylicacid ethyl ester;trans-1-methylamino-1,2,11,11a-tetrahydro-6H-benzo[f]indeno[1,7-bc]azepine;andtrans-1-methylamino-1,2,3,7,12,12a-hexahydrobenzo[f]naphth[1,8-bc]azepine.